LJMU Research Online Wallach, J, Colestock, T, Cicali, B, Elliott, SP, Kavanagh, PV, Adejare, A, Dempster, NM and Brandt, SD Syntheses and analytical characterizations of N-alkyl-arylcyclohexylamines. http://researchonline.ljmu.ac.uk/id/eprint/3240/ Article Citation (please note it is advisable to refer to the publisher’s version if you intend to cite from this work) Wallach, J, Colestock, T, Cicali, B, Elliott, SP, Kavanagh, PV, Adejare, A, Dempster, NM and Brandt, SD (2015) Syntheses and analytical characterizations of N-alkyl-arylcyclohexylamines. Drug Testing and Analysis. ISSN 1942-7611 LJMU has developed LJMU Research Online for users to access the research output of the University more effectively. Copyright © and Moral Rights for the papers on this site are retained by the individual authors and/or other copyright owners. Users may download and/or print one copy of any article(s) in LJMU Research Online to facilitate their private study or for non-commercial research. 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For more information please contact [email protected] http://researchonline.ljmu.ac.uk/ Drug Testing and Analysis Syntheses and analyti cal characterizations of N -alkyl - arylcyclohexylamines Journal:For Drug Peer Testing and Analysis Review Manuscript ID: DTA-15-0185.R1 Wiley - Manuscript type: Research Article Date Submitted by the Author: n/a Complete List of Authors: Wallach, Jason; University of the Sciences, Department of Pharmaceutical Sciences Colestock, Tristan; University of the Sciences, Department of Pharmaceutical Sciences Cicali, Brian; University of the Sciences, Department of Pharmaceutical Sciences Elliott, Simon; ROAR Rorensics, Kavanagh, Pierce; School of Medicine, Trinity Centre for Health Sciences, St. James Hospital, Department of Pharmacology and Therapeutics Adejare, Adeboye; University of the Sciences, Department of Pharmaceutical Sciences Dempster, Nicola; Liverpool John Moores University, School of Pharmacy and Biomolecular Sciences Brandt, Simon; School of Pharmacy & Biomolecular Sciences , Liverpool John Moores University New psychoactive substances, Research chemicals, Phencyclidine, NMDA Keywords: receptors, Arylcyclohexylamines The rise in new psychoactive substances that are available as ‘research chemicals’ (RCs) remains a significant forensic and legislative challenge. A number of arylcyclohexylamines have attracted attention as RCs and continued to be encountered, including 3-MeO-PCP, 3-MeO-PCE and 3- MeO-PCPr. These compounds are commonly perceived as ketamine-like dissociative substances and are believed to act predominantly via antagonism of the N-methyl-D-aspartate (NMDA) receptor. To aid in the identification of newly emerging substances the syntheses of fifteen N- alkyl-arylcyclohexylamines are described. Analytical characterizations were Abstract: performed via gas chromatography and high performance liquid chromatography coupled to multiple forms of mass spectrometry as well as nuclear magnetic resonance spectroscopy, ultraviolet diode array detection and infrared spectroscopy. The series consisted of the N-alkyl derivatives (N-methyl, N-ethyl, N-propyl) of phenyl-substituted and isomeric 2-, 3- and 4-methoxy phenylcyclohexylamines, as well as the N-alkyl derivatives obtained from a 3-methylphenyl and 2-thienyl moiety. In addition to the presentation of a range of previously unreported data, it was also found that positional isomers of aryl methoxyl-substituted arylcyclohexylamines were readily distinguishable under a variety of analytical conditions. http://mc.manuscriptcentral.com/dta Page 1 of 34 Drug Testing and Analysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 http://mc.manuscriptcentral.com/dta Drug Testing and Analysis Page 2 of 34 1 2 3 Syntheses and analytical characterizations of N-alkyl- 4 5 arylcyclohexylamines 6 7 Jason Wallach a, Tristan Colestock a, Brian Cicali a, Simon P. Elliott b, Pierce 8 V. Kavanagh c, Adeboye Adejare a, Nicola M. Dempster d, Simon D. Brandt d,* 9 10 11 a 12 Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of 13 the Sciences, Philadelphia, PA 19104, USA 14 15 b ROAR Forensics, Malvern Hills Science Park, Geraldine Road, WR14 3SZ, UK 16 17 c Department of Pharmacology and Therapeutics, School of Medicine, Trinity Centre for 18 Health Sciences,For St. James Hospital,Peer Dublin 8, IrelanReviewd 19 20 d School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom 21 22 Street, Liverpool L3 3AF, UK 23 24 25 *Correspondence to: Simon D. Brandt, School of Pharmacy and Biomolecular Sciences, 26 Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, UK. E-Mail: 27 [email protected] 28 29 Running title: Characterization of N-alkyl-arylcyclohexylamines 30 31 32 33 Abstract 34 35 The rise in new psychoactive substances that are available as ‘research chemicals’ 36 37 (RCs) remains a significant forensic and legislative challenge. A number of 38 arylcyclohexylamines have attracted attention as RCs and continued to be 39 encountered, including 3-MeO-PCP, 3-MeO-PCE and 3-MeO-PCPr. These 40 compounds are commonly perceived as ketamine-like dissociative substances and 41 are believed to act predominantly via antagonism of the N-methyl-D-aspartate 42 43 (NMDA) receptor. To aid in the identification of newly emerging substances the 44 syntheses of fifteen N-alkyl-arylcyclohexylamines are described. Analytical 45 characterizations were performed via gas chromatography and high performance 46 liquid chromatography coupled to multiple forms of mass spectrometry as well as 47 nuclear magnetic resonance spectroscopy, ultraviolet diode array detection and 48 infrared spectroscopy. The series consisted of the N-alkyl derivatives ( N-methyl, N- 49 50 ethyl, N-propyl) of phenyl-substituted and isomeric 2-, 3- and 4-methoxy 51 phenylcyclohexylamines, as well as the N-alkyl derivatives obtained from a 3- 52 methylphenyl and 2-thienyl moiety. In addition to the presentation of a range of 53 previously unreported data, it was also found that positional isomers of aryl methoxyl- 54 substituted arylcyclohexylamines were readily distinguishable under a variety of 55 analytical conditions. 56 57 58 59 60 http://mc.manuscriptcentral.com/dta 1 Page 3 of 34 Drug Testing and Analysis 1 2 3 Keywords: New psychoactive substances; ‘research chemicals’; phencyclidine; 4 NMDA receptors; arylcyclohexylamines 5 6 7 Introduction 8 9 The non-medical use of dissociative drugs including 1-(1-phenylcyclohexyl)piperidine 10 (PCP), ketamine and their derivatives is a challenge to policy makers, clinicians and 11 forensic investigators charged with their identification. More recent examples of 12 13 dissociative drugs include ‘research chemicals’ (RCs) such as 3-MeO-PCP, [1-4] 14 methoxetamine (MXE), diphenidine and 2-methoxydiphenidine (2-MXP). In the UK, 15 a range of arylcyclohexylamines were placed under control in 2013 following generic 16 legislation [5] but control status varies across the globe. Within one week of 17 introducing generic control, diphenidine was available for purchase in the UK, which 18 For Peer Review 19 added to the existing product catalogues of substances suspected to show [1] 20 dissociative properties in humans. The association of some those newly emerging 21 substances with acute toxicity [6-8] serves as a reminder that the accurate identification 22 of these substances is essential for the monitoring of new psychoactive 23 substances.[9,10] 24 25 26 The major pharmacological mechanism that appears to mediate a significant portion 27 of the therapeutically relevant and psychoactive effects of dissociative substances 28 includes uncompetitive antagonism of the N-methyl-D-aspartate (NMDA) receptor. 29 NMDA receptor antagonists exemplify an important pharmacological class that 30 provides promising pharmacological tools. They are used or are being investigated in 31 a number of therapeutic areas including general anesthetics, neuroprotection, 32 [1,11,12] 33 management of neuropathic pain and depression. Issues linked with clinical 34 tolerability remain challenging for clinical development of this promising 35 pharmacological class.[1,13,14] 36 37 Recently a study of the receptor binding profiles of a series of dissociative legal highs 38 included 3-methoxyeticyclidine (3-MeO-PCE) ( 3b ).[15] Consistent with reports of its 39 [1] 3 40 potent dissociative effects in humans it showed high affinity for (+)-[ H]MK-801 41 labeled NMDA receptors (61 nM). In addition, affinity for the serotonin transporter 42 (115 nM) and lesser affinity at sigma-1 and sigma-2 receptor sites were observed. [15] 43 It is unknown how these additional pharmacological interactions may contribute to 44 the psychoactive properties of 3-MeO-PCE and related arylcyclohexylamines and 45 46 further studies are warranted to explore polypharmacological mechanisms that may 47 be relevant as well. 48 49 N-Alkyl-arylcyclohexylamines including PCE, PCPr and PCiP (Figure 1) were sold on 50 ‘street markets’ during the 1960-1990s in the United States and PCE